Our objective is to study the pathophysiological basis of congenital murine hydrocephalus in the hy-3 and ch strains as models, so as to understand congenital human hydrocephalus. We are investigating the etiology of hydrocephalus in both of these mutants. Specifically, we are studying the 1) cranium, 2) meninges and subarachnoid space, 3) brain parenchyma, 4) ventricular system, 5) ependymal cells, and 6) choroid plexus in fetal, newborn, and adult normal and hydrocephalic mice. In addition to light and electron microscopic techniques for the study of these tissues, we will utilize 1) ultrastructurally visible tracers, to investigate CSF dynamics; 2) histochemical methods, to characterize substances in the extracellular space of cerebral tissue and in the matrix of cartilaginous bone; 3) biochemical procedures, to analyze the acidic glycosaminoglycan content in normal and hydrocephalic mice; 4) fluorescent techniques to evaluate vascular permeability; 5) electrophysiology, to monitor pressure and estimate extracellular space changes. In the ch strain, our hydrocephalic and normal litter-mate mice are obtained by Caesarean section, since affected animals of this strain die at birth. We have introduced in the hy-3 strain a dominant marker (Os) gene which is recognizable in midfetal life; this facilitates identification of hy-3 homozygotes in utero and in the early postnatal period, before this type of hydrocephalus begins to develop. We will correlate our finding of abnormalities - anatomic, histologic, biochemical, and functional - with our clinical studies on hydrocephalic children.